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Published on: March 31, 2018
Mitochondrial signatures of infant mesenchymal stem cells predict child adiposity: The Healthy Start Study
Lauren E Gyllenhammer1, Madeline Rose Keleher2, Cheyret Wood2
1University of California, Irvine.
Insights
Newborn mesenchymal stem cell (MSC) gene expression and DNA methylation at birth are linked to childhood obesity risk. Early-life mitochondrial pathways in MSCs may predict future fat mass accretion.
Area of Science:
- Genetics and Epigenetics
- Developmental Biology
- Metabolic Health
Background:
- Obesity is multifactorial, with early-life factors influencing risk.
- Mesenchymal stem cells (MSCs) are key progenitors for body composition.
- Identifying molecular signatures at birth can inform prevention strategies.
Purpose of the Study:
- To investigate associations between newborn MSC transcriptomic and DNA methylation profiles and childhood adiposity.
- To explore the role of molecular pathways in early-life susceptibility to obesity.
Main Methods:
- Analyzed transcriptomic (RNAseq) and DNA methylation (Illumina EPIC) of umbilical cord-derived MSCs from 140 mother/child dyads.
- Measured childhood adiposity (%fat mass) using air displacement plethysmography at birth, infancy, and early childhood.
- Utilized Geneset Enrichment Analysis and targeted methylation analysis.
Main Results:
- 302 MSC transcripts associated with adiposity across early life (FDR<0.05).
- Mitochondrial pathways (Complex I, fatty acid beta-oxidation, TCA cycle) downregulated in MSCs linked to higher adiposity.
- DNA methylation in specific CpGs and the HDAC4 gene region associated with adiposity.
Conclusions:
- Newborn MSC transcriptomic and methylation profiles are associated with adiposity development through early childhood.
- Early-life mitochondrial signatures in MSCs may indicate biological susceptibility to increased fat mass.
- Findings highlight the potential of molecular profiling at birth for obesity risk prediction.
Importance:
Although obesity risk is multifactorial, identification of molecular pathways at birth may reveal early-life susceptibility, guiding prevention and intervention efforts.
Objective:
We measured transcriptional and DNA methylation profiles of umbilical cord-derived mesenchymal stem cells (MSCs), which are progenitors for body composition (e.g., adipose, muscle), and tested associations with childhood adiposity over the first 4-6yr of life.
Design:
Among 140 mother/child dyads enrolled in The Healthy Start Cohort Study, MSCs were isolated at birth and analyzed for their transcriptomic (RNAseq) and DNA methylation profile (Illumina EPIC). We measured newborn (24-72hrs after birth, n=134), infant (4-6mo, n=128), and early childhood (4-6yr, n=81) adiposity (%fat mass [%FM]) with air displacement plethysmography. A parallel in vitro adiposity phenotype was modeled as triglyceride accumulation during MSC adipogenesis.
Setting:
Prenatal obstetrics clinics at the University of Colorado Hospital in 2010-2014. Follow-up of women and children is ongoing.
Participants:
Singleton infants born to healthy women across the BMI spectrum.
Exposure:
Newborn MSC transcriptome.
Main Outcome:
Infant/childhood adiposity (%FM).
Results:
302 MSC transcripts were associated with %FM at birth, infancy and early childhood (p=5, p=296 and p=1), respectively [false discovery rate, FDR<0.05]). Geneset Enrichment Analysis of transcriptome data revealed 670 pathways associated with %FM (FDR<0.05, p=3 at birth, p=267 infancy, p=400 early childhood). Gene sets involved in extracellular matrix organization, were positively associated, while mitochondrial fatty acid beta-oxidation, the citric acid (TCA) cycle, cell cycle and chromosome/telomere maintenance were negatively associated with adiposity at 4-6mo and 4-6yr (FDR<0.05). Mitochondrial complex I pathways downregulation was associated with higher in vivo adiposity at all three timepoints (FDR<0.05), and with in vitro adiposity (p<0.05). We examined shared core enrichment genes between infant and early childhood pathways (p=664), as input for targeted methylation analysis. Of these shared genes, DNA methylation in four CpGs (FDR<0.2) and one noteworthy gene region, HDAC4 (FDR=0.055), associated with %FM in infancy and early childhood, respectively.
Conclusions And Relevance:
Newborn MSC transcriptomic and methylation features, particularly within mitochondrial pathways, were associated with adiposity through early childhood. These findings suggest that early-life mitochondrial signatures may predict biological susceptibility to greater fat mass accretion.
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